The ability to produce images of the inside of a living organism without invasive surgery has been a major advancement in medicine over the last one hundred years. Imaging techniques such as X-ray computer tomography (CT) and magnetic resonance imaging (MRI) have given doctors and scientists the ability to view high-resolution images of anatomical structures inside the body. While this has led to advancements in disease diagnosis and treatment, a large set of diseases cause changes in anatomical structure only in the late stages of the disease, or never at all. This has given rise to a branch of medical imaging that captures certain metabolic activities inside a living body. Positron emission tomography (PET) is in this class of medical imaging.
Positron Emission Tomography
PET is a medical imaging modality that takes advantage of radioactive decays to measure certain metabolic activities inside living organisms. PET imaging systems comprise three main components, indicated schematically in FIG. 1, a radioactive tracer that is administered to the subject to be scanned, a scanner that is operable to detect the location of radioactive tracer (indirectly as discussed below), and a tomographic imaging processing system.
The first step is to produce and administer a radioactive tracer 90, comprising a radioactive isotope and a metabolically active molecule. The tracer 90 is injected into the body to be scanned 91. After allowing time for the tracer 90 to concentrate in certain tissues, the body 91 is suitably positioned inside the scanner 92. The radioactive decay event for tracers used in PET studies is positron emission. An emitted positron travels a short distance in the body tissue until it interacts with an electron. The positron-electron interaction in an annihilation event that produces two 511 KeV anti-parallel photons. The scanner 92 is adapted to detect at least some of the photons from the annihilation event.
The scanner 92, the second component of PET system, includes a ring of sensors that detect the 511 KeV photons, and front-end electronics that process the signals generated by the sensors. The sensors typically comprise scintillator crystals, or scintillators 93 and photomultiplier tubes (PMT), silicon photomultipliers (SiMP) or avalanche photo diodes (APD) 94. The scintillator crystal 93 converts the 511 KeV high-energy photons into many lower-energy photons, typically visible light photons. The PMT, SiMP or APD 94 detect the visible light photons and generate a corresponding electrical pulse. The PMT pulses are processed by front-end electronics to determine the parameters or characteristics of the pulse (i.e., energy, timing). For convenience, references to PMT herein will be understood to include any mechanism or device for detecting high-energy photons, such as 511 KeV photons, and producing lower-energy photons, such as visible light photons, in response.
Finally, the data is sent to a host computer 95 that performs tomographic image reconstruction to turn the data into a 3-D image.
Radiopharmaceutical
To synthesize the tracer 90, a short-lived radioactive isotope is attached to a metabolically active molecule. The short half-life reduces the subject's exposure to ionizing radiation, but generally requires the tracer 90 be produced close to the scanner. The most commonly used tracer is fluorine-18 flourodeoxyglucose ([F-18]FDG), an analog of glucose that has a half-life of 110 minutes. [F-18]FDG is similar enough to glucose that it is phosphorylated by cells that utilize glucose, but does not undergo glycolysis. Thus the radioactive portion of the molecule becomes trapped in the tissue. Cells that consume a lot of glucose, such as cancers and brain cells, accumulate more [F-18]FDG over time relative to other tissues.
After sufficient time has passed for the tissue of interest to uptake enough tracer 90, the scanner 92 is used to detect the radioactive decay events, i.e., by detecting the 511 KeV photons. When a positron is emitted, it typically travels a few millimeters in tissue before it annihilates with an electron, producing two 511 KeV photons directed at 180°±0.23° from one another.
Photon Scintillation
A 511 KeV photon has a substantial amount of energy and will pass through many materials, including body tissue. While this typically allows the photon to travel through and exit the body, the high-energy photons are difficult to detect. Photon detection is the task of the scintillator 93. A scintillator 93 absorbs high-energy photons and emits lower energy photons, typically visible light photons. A scintillator 93 can be made from various materials, including plastics, organic and inorganic crystals, and organic liquids. Each type of scintillator has a different density, index of refraction, timing characteristics, and wavelength of maximum emission.
In general, the density of the scintillator crystal determines how well the material stops the high-energy photons. The index of refraction of the scintillator crystal and the wavelength of the emitted light affect how easily light can be collected from the crystal. The wavelength of the emitted light also needs to be matched with the device that will turn the light into an electrical pulse (e.g., the PMT) in order to optimize the efficiency. The scintillator timing characteristics determine how long it takes the visible light to reach its maximum output (rise time) and how long it takes to decay (decay time). The rise and decay times are important because the longer the sum of these two times, the lower the number of events a detector can handle in a given period, and thus the longer the scan will take to get the same number of counts. Also, the longer the timing characteristics, the greater the likelihood that two events will overlap (pile-up) and data will be lost.
An exemplary modern scintillator material is Lu2SIo5(Ce), or LSO, which is an inorganic crystal. LSO has a reported rise constant of 30 ps and a decay constant of 40 ns. The reported times can vary slightly due to variations in the geometry of the crystal and the electronics that are attached to it. LSO is a newer scintillator material that exhibits fast response and good light output.
Photomultiplier Tubes
Attached to the scintillator 93 are electronic devices that convert the visible light photons from the scintillator 93 into electronic pulses. The two most commonly used devices are PMTs and APDs. A PMT is a vacuum tube with a photocathode, several dynodes, and an anode that has high gains to allow very low levels of light to be detected. APDs are a semiconductor version of the PMT. Another technology that is currently being studied for use in PET scanners is SiPMs. SiPMs comprise an array of semiconducting photodiodes that operate in Geiger mode so that when a photon interacts and generates a carrier, a short pulse of current is generated. In an exemplary SiPM, the array of photodiodes comprises about 103 diodes per mm2. All of the diodes are connected to a common silicon substrate so the output of the array is a sum of the output of all of the diodes. The output can therefore range from a minimum wherein one photodiode fires to a maximum wherein all of the photodiodes fire. This gives theses devices a linear output even though they are made up of digital devices.
An exemplary system uses a PMT having twelve channels: six in the ‘x’ direction and six in the ‘y’ direction, as depicted in FIG. 2. The separate channels allow for more accurately determining the location of an event. For example, if an event is detected in the upper left hand corner of the PMT, then channels Y1 and X1 will have a large signal, with progressively smaller signals at each successively larger channel number. Channels Y6 and X6 will have virtually no signal.
When enough coincidental events have been detected, image reconstruction can begin. Essentially the detected events are separated into parallel lines of response (interpreted path of photon pair), that can be used to create a 3-D image using computer tomography.
While PET, MRI, and CT are all common medical imaging techniques, the information obtained from the different modalities is quite different. MRI and CT give anatomical or structural information. That is, they produce a picture of the inside of the body. This is great for problems such as broken bones, torn ligaments or anything else that presents as abnormal structure. However, MRI and CT do not indicate metabolic activity. This is the domain of PET. The use of metabolically active tracers means that the images produced by PET provide functional or biochemical information.
Oncology (study of cancer) is currently the most common application of PET. Certain cancerous tissues metabolize more glucose than normal tissue. [F-18]FDG is close enough to glucose that cancerous cells readily absorb it, and therefore they have high radioactive activity relative to background tissue during a scan. This enables a PET scan to detect some cancers before they are large enough to be seen on an MRI scan. PET scan information is also very useful for monitoring treatment progression, as the quantity of tracer uptake can be tracked over the progression of the therapy. If a scan indicates lower activity in the same cancerous tissue after therapy, it indicates the therapy is working.
PET is also useful in neurology (study of the nervous system) and cardiology (study of the heart). An interesting application in neurology is the early diagnosis of Parkinson's disease. Tracers have been developed that concentrate in the cells in the brain that produce dopamine, a neurotransmitter. In patients with Parkinson's disease, neurons that produce dopamine reduce in number. So, a scan of a Parkinson's patient would have less activity than a healthy patient. This can lead to early diagnosis, since many of the other early signs of Parkinson's are similar to other diseases.
There remains a need for continued improvements in the cost, efficiency and accuracy of PET systems.